T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. Clinical trials with TCR gene-modified T cells have shown that objective clinical responses can be obtained for patients with advanced malignancies. Similar approaches are in development for treatment of infectious disease. However, there is considerable debate over the nature of the TCR to be used in engineered T cells, and whether naturally occurring TCRs can be improved. Emphasis has been on identifying natural ?high affinity? TCRs, and these have been emphasized in clinical trials. As T cell potency can sometimes be strengthened with the affinity of the TCR for antigen, there have also been efforts to use TCRs engineered for enhanced antigen affinity in immunotherapy. However, adverse events, including deaths, have occurred in some trials with gene-modified T cells. In some cases, this is clearly attributable to TCR cross-reactivity. Moreover, as high affinity can curtail function and low affinity TCRs are clearly functional, the presumption that improved TCR affinity is better for immunotherapy is questionable. In the parent proposal, an ambitious program asking how to build better TCRs for immunotherapy is underway. This diversity supplement requests additional funds to support Dr. Jesus Alonso, a Hispanic- American university administrator and molecular virologist who is returning to laboratory science in an effort to shift his career towards a research track. Dr. Alonso will embark on a set of studies to extend the parent project, asking if and how the program proposed in the parent project can be applied to different, clinically relevant TCRs. Dr. Alonso will study the TIL1383I TCR, which has been used in a melanoma clinical trial, asking whether a more potent but still safe TIL1383I TCR variant can be generated via structure guided design. Support for Dr. Alonso will help improve diversity in NIH-supported science and directly advance the development of TCR based cell immunotherapy. Via an ambitious career development plan, Dr. Alonso will progress rapidly scientifically and professionally to the point where, via his own research, he can further the successful recruitment of under-represented minorities to the US-based biomedical research enterprise.